This R01 application seeks to conduct a case-control genetic association study of opioid dependence with inclusion of childhood trauma history as a risk modifying variable. Cases (N=1500) will be ascertained from the large methadone (and buprenorphine) maintenance treatment population of New South Wales, Australia. Controls (N=1500) will be ascertained via employment offices and medical clinics in proximity to areas where maintenance treatment is provided. The project s aims are as follows: AIM 1 To interview and collect blood samples from 1500 opioid dependent individuals and 1500 matched controls. AIM 2 To identify polymorphisms and/or mutations in candidate genes to be typed in cases and controls. AIM 3 To assess retrospectively history of childhood trauma to enable its inclusion as a risk modifying variable. AIM 4 To analyze genotype and interview data to test for candidate gene effects on opioid dependence, and their moderation by history of childhood trauma. The latter analyses will target genes whose products are known from Prior research to be involved in: (i) stress-sensitive mediation of the perceived positive effects of opioids; (ii) stress-induced opioid relapse; and (iii) opioid regulation of the stress response. The design seeks to improve upon prior work by: 1) undertaking the investigation in a sample of adequate size several-fold larger than the largest of prior association studies of opioid dependence) to provide substantial power; 2) using a well-defined, well-characterized phenotype (i.e. the DSM-IV diagnosis of opioid dependence nade via in person interview using the CIDI, an instrument with established reliability and validity); 3) applying conservative corrections for multiple testing; 4) employing genomic controls to control for population stratification; and 5) incorporating childhood abuse history as a risk modifying variable in analyses to determine whether evidence is found for significant G x E interactions. Candidate gene selection will be based on information gleaned from animal and human studies, focusing on reports of association with opioid dependence and related phenotypes as well as studies that have demonstrated persistent pathophysiologic changes in adult animals and humans with a history of early trauma. Single nucleotide polymorphisms (SNPs) of adequate frequency will be located by searching available databases with preference given to functional polymorphisms ant hose for whom prior studies have reported association.